Single cell analysis using secondary ion mass spectrometry

Abstract

A method of analyzing a population of cells is disclosed. In certain embodiments, the method includes i) obtaining an array of cells on a substrate, wherein the cells are labeled with one or more mass tags and are separated from one another, ii) measuring, using secondary ion mass spectrometry (SIMS), the abundance of the one or more mass tags at a plurality of locations occupied by the cells, thereby generating, for each individual cell measured, a set of data, and iii) outputting the set of data for each of the cells analyzed. Also provided herein are systems that find use in performing the subject method. In some embodiments, the system is an automated system for analyzing a population of cells using SIMS.

What is claimed is: 
     
       1. A method of analyzing a cell, comprising:
 obtaining a cell on a substrate, wherein the cell is labeled with a plurality of mass tags; measuring, using mass spectrometry, an abundance of each of the plurality of mass tags at a plurality of sites for each of a plurality of depths within the cell, thereby generating a set of data, wherein the abundance of each of the plurality of mass tags at a plurality of sites for each of a plurality of depths within the cell is measured using secondary ion mass spectrometry (SIMS). 
 
     
     
       2. The method of  claim 1 , wherein the measuring step comprises applying a SIMS ion beam with a diameter equal to or less than half the diameter of the cell. 
     
     
       3. The method of  claim 2 , wherein the SIMS ion beam has a diameter in the range of 1 μm to 50 μm. 
     
     
       4. The method of  claim 1 , wherein the measuring step comprises applying a plurality of pulses of a SIMS ion beam at each of the plurality of sites to obtain measurements of the abundance of the plurality of mass tags at the plurality of depths for each of the different sites. 
     
     
       5. The method of  claim 4 , wherein the SIMS ion beam has a diameter in the range of 10 nm to 1500 nm. 
     
     
       6. The method of  claim 1 , further comprising providing the set of data as a three-dimensional image showing subcellular localization of the plurality of mass tags within the cell. 
     
     
       7. The method of  claim 1 , wherein the cell is labelled by administering the plurality of mass tags to an animal subject and obtaining a labeled cell from the animal subject. 
     
     
       8. The method of  claim 1 , wherein the method comprises:
 labeling the cell with a first mass tag and a second mass tag, wherein the first mass tag localizes to a known subcellular structure of the cell; 
 measuring the abundance of the first and second mass tags at the plurality of sites and depths within the cell; and 
 determining the subcellular localization of the second mass tag based on the relative measured abundance of the first and second mass tags at the plurality of sites and depths. 
 
     
     
       9. The method of  claim 1 , wherein the abundance of the plurality of mass tags is measured with a depth resolution in the range of about 0.02% to about 50% of the depth of the cell. 
     
     
       10. The method of  claim 1 , wherein the abundance of the plurality of mass tags is measured with a depth resolution in the range of about 1 nm to about 50,000 nm. 
     
     
       11. The method of  claim 1 , wherein the cell is obtained from a blood sample. 
     
     
       12. The method of  claim 11 , wherein the cell is selected from the group consisting of a platelet, an erythrocyte, a neutrophil, a lymphocite, an eosinophil, a basophil, and a monocyte. 
     
     
       13. The method of  claim 1 , further comprising outputting the set of data for the one or more cells. 
     
     
       14. The method of  claim 13 , wherein the set of data is output as a three-dimensional image showing subcellular localization of the plurality of mass tags within the cell. 
     
     
       15. A system for analyzing a cell, the system comprising:
 a mass spectrometer and a holder for retaining a substrate having a cell disposed thereon, wherein the cell is labeled with a plurality of mass tags, the system programmed to:
 measure the abundance of the plurality of mass tags at a plurality of sites for each of a plurality of depths within the cell by detecting secondary ions generated from the sample; and 
 generate a data set comprising the abundance of the plurality of mass tags at the plurality of sites and depths within the cell based on the detected secondary ions. 
 
 
     
     
       16. The system of  claim 15 , further comprising a secondary ion mass spectrometry (SIMS) ion beam source. 
     
     
       17. The system of  claim 16 , further operable to apply a plurality of pulses of a SIMS ion beam at each of the plurality of sites to obtain measurements of the abundance of the plurality of mass tags at the plurality of depths for each of the different sites. 
     
     
       18. The system of  claim 15 , further operable to provide the data set for the cell as a three-dimensional image of subcellular localization of the plurality of mass tags within the cell.